Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo
Open accessAbstract
Significance: Alzheimer's disease is pathologically characterized by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (NFTs). It has long been assumed that the accumulation of tau into NFTs causes neuronal dysfunction and death, and is a proximate cause of dementia in patients with Alzheimer’s disease. This assumption underlies the NFT-busting drugs currently in clinical trials and research efforts aimed at understanding tau aggregation. Our study tested the dogma that NFT-bearing neurons are indeed impaired in their ability to respond to complex sensory stimuli. Using two-photon imaging in awake mice with NFT pathology, we found that individual neurons with NFTs respond to visual stimuli and do not impair local circuits. These unexpected results suggest that the presence of an NFT does not inevitably lead to gross physiological alterations.
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The neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau.
“suggesting that the neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau [11–14].”
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- Authors
- Kuchibhotla, K. V., Wegmann, S., Kopeikina, K. J., Hawkes, J., Rudinskiy, N., Andermann, M. L., Spires-Jones, T. L., Bacskai, B. J., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Boston University (US)
- Beth Israel Deaconess Medical Center (US)
- Alzheimer’s Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-12-24
- Volume
- 111
- Issue
- 1
- Pages
- 510-514
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3890777
- OpenAlex
- W2069481882
- Cited by
- 193
- References
- 5
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 11 · 2023: 21 · 2022: 14 · 2021: 13 · 2020: 18 · 2019: 19 · 2018: 11 · 2017: 15 · 2016: 9 · 2015: 26 · 2014: 15
- FWCI
- 11.58
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- other-oa
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute on Aging (R01AG026249, P50AG005134, P30AG062421)
- National Institute of Biomedical Imaging and Bioengineering (EB 000768, R01EB000768)
- National Center for Research Resources (S10RR025645)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- neurofibrillary tangles, tau protein, Alzheimer's disease, tauopathy, P301L tau, rTg4510 mice, visual cortex, neuronal function, orientation selectivity, direction selectivity, dendritic integration, cortical circuits, in vivo calcium imaging
- MeSH terms
- Dependovirus, Alzheimer Disease, Animals, Brain, Calcium, Humans, Image Processing, Computer-Assisted, Mice, Transgenic, Microscopy, Fluorescence, Models, Neurological, Mutation, Neurons, Neurofibrillary Tangles, tau Proteins, Photons, Transgenes, Tauopathies, Mice
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